Water-soluble PDE4 inhibitors for the treatment of dry eye.

PDE4 inhibitors have the potential to alleviate the symptoms and underlying inflammation associated with dry eye. Disclosed herein is the development of a novel series of water-soluble PDE4 inhibitors. Our studies led to the discovery of coumarin 18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.

Human conjunctival epithelial cell responses to platelet-activating factor (PAF): signal transduction and release of proinflammatory cytokines.

Purpose: The aims of the study were to characterize the signal transduction responses to platelet-activating factor (PAF) and to monitor the downstream effects of PAF on the production of proinflammatory cytokines in human conjunctival epithelial cells (HCECs).

Methods: The generation of inositol phosphates ([(3)H]IPs) from [(3)H]phosphoinositide (PI) hydrolysis and the mobilization of intracellular calcium ([Ca(2+)](i)) were evaluated using ion exchange chromatography and Fura-2 fluorescence techniques, respectively. The production of the cytokines (interleukin-6 [IL-6], interleukin-8 [IL-8], and granulocyte macrophage colony-stimulating factor [GM-CSF]) from PAF-stimulated HCECs was quantified using specific ELISA assays.

MUC16 expression in Sjogren's syndrome, KCS, and control subjects.

Purpose: To investigate the expression of MUC16 protein in tears and conjunctival cell membranes and MUC16 mRNA in conjunctival cells of Sjogren's syndrome (SS), keratoconjunctivitus sicca (KCS) and non-dry eyed (NDE) subjects. The relationship of tear flow and soluble MUC16 concentration was also measured.

Methods: Seventy-six subjects were recruited for this study: 25 SS (confirmed via American-European Consensus Criteria 2002), 25 KCS (confirmed by symptoms and Schirmer scores < or =10 mm) and 26 NDE.

Preservation of tear film integrity and inhibition of corneal injury by dexamethasone in a rabbit model of lacrimal gland inflammation-induced dry eye.

Purpose: The aim of this study was to establish a clinically relevant short-term animal model of dry eye with utility in identifying compounds with potential therapeutic efficacy.

Methods: Rabbit lacrimal glands were injected with the T-cell mitogen Concanavalin A (Con A) and inflammation, tear function, and corneal epithelial cell integrity were subsequently assessed. The inflammatory response was characterized by quantifying biochemical markers of inflammation ex vivo and by confirming inflammatory cell influx by histology.

Preclinical and clinical antiallergic effect of olopatadine 0.2% solution 24 hours after topical ocular administration.

Pharmacologic studies examined the potential of a solution containing olopatadine to maintain and extend antiallergic efficacy after single topical ocular drop administration over 24 hours. Results of these preclinical experiments conducted in guinea pigs indicated that olopatadine 0.2% (wt/vol) solution was significantly effective 24 hours after dosing.

AL-2512, a novel corticosteroid: preclinical assessment of anti-inflammatory and ocular hypertensive effects.

The anti-inflammatory efficacy and ocular hypertensive effect of AL-2512 were characterized in rodent and feline models of ocular inflammation. Neutrophil influx into ocular tissue following topical ocular administration of test drugs was evaluated in models of endotoxin-induced uveitis. In rats, the anti-inflammatory efficacy of AL-2512 was compared with that of 0.

Corneal protection by the ocular mucin secretagogue 15(S)-HETE in a rabbit model of desiccation-induced corneal defect.

The mucin secretagogue 15(S)-HETE was found to stimulate glycoprotein secretion in human ocular tissue at submicromolar concentrations in the present studies. Therefore, the ability of topically applied 15(S)-HETE to preserve corneal integrity was investigated in a rabbit model of desiccation-induced corneal defect. Desiccation-induced corneal injury was elicited in anesthetized rabbits by maintaining one eye open with a speculum.